Some people come through Covid-19 with barely any flu-like symptoms, but for some individuals it spirals into serious illness, disability and even death in others.
This puzzling peculiarity of Covid makes researchers try to identify those people who are most at risk of complications from the SARS-CoV-2 virus.
Now, researchers at Rockefeller University (USA) have shown in mice that those with genetic variants previously linked to Alzheimer’s disease had a higher risk of dying when infected with Covid-19.
A retrospective analysis suggests that patients with those same genetic variants were more likely to die from Covid-19 throughout the pandemic.
Given that 3% of the world’s population carry these genetic variants, the findings may have implications for hundreds of millions of individuals worldwide.
“It is clear that age, gender and certain pre-existing conditions, such as diabetes, increase the risk of harmful outcomes, but these factors do not fully explain the spectrum of Covid outcomes,” says Sohail Tavazoie.
In previous work, Tavazoie’s lab studied the APOE gene, which plays a role in cancer metastasis. After showing that the gene suppresses the spread of melanoma and regulates anti-tumor immune responses, he and his team began to take a closer look at its different forms, or alleles. Most people have a form called APOE3, but 40% of the population carry at least one copy of the APOE2 or APOE4 variant. Individuals with APOE2 or APOE4 produce proteins that differ from the APOE3 protein by one or two amino acids.
One or two amino acids make a difference. Individuals with APOE4 are at increased risk of developing Alzheimer’s and atherosclerosis, and Tavazoie and Benjamin Ostendorf, a postdoctoral fellow in their lab, have shown that APOE4 and APOE2 influence the immune response against melanoma. As the pandemic progressed, Tavazoie and Ostendorf began to wonder if APOE variants might also influence Covid outcomes. “We had only looked at non-infectious diseases,” she says. “But what if APOE variants also made people vulnerable to an infectious agent, like SARS-CoV-2? Could they elicit different immune responses against a virus?
A difference of only one or two amino acids in the APOE gene was enough to cause important differences in the survival of the mice that presented Covid.
To find out, Tavazoie and colleagues first exposed more than 300 human APOE mice to a mouse-adapted version of SARS-CoV-2 produced by colleagues Hans-Heinrich Hoffmann and Charles M. Rice. They found that mice with APOE4 and APOE2 were more likely to die than those with the more common APOE3 allele. “The results were surprising,” says Ostendorf, lead author of the study. “A difference of only one or two amino acids in the APOE gene was enough to cause important differences in the survival of the mice that presented Covid.”
The APOE2 and APOE4 mice also had more virus replicating in their lungs, and more signs of inflammation and tissue damage. At the cellular level, the researchers found that APOE3 appeared to reduce the amount of virus entering the cell, while animals with the other variants had less potent immune responses to the virus. “Taken together, these results suggest that the APOE genotype influences COVID outcomes in two ways, modulating the immune response and preventing SARS-CoV-2 from infecting cells,” says Ostendorf.
The lab then turned to retrospective studies in humans. In an analysis of 13,000 UK Biobank patients, they found that individuals with two copies of APOE4 or APOE2 were more likely to die from COVID than those with two copies of APOE3. (Approximately 3% of individuals have two copies of APOE2 or APOE4, which represents about 230 million people worldwide.)
However, Tavazoie stresses that there is no evidence that the 40% of individuals who have only one of these alleles are at increased risk. In addition, she says that people with two APOE2 or APOE4 alleles are probably at lower risk than the data indicates. “Vaccination changes the landscape,” she explains. “The UK Biobank data covers the entire duration of the pandemic, and many of the individuals who died early on would likely have been protected if they had been vaccinated.”
Looking ahead, Tavazoie hopes that prospective studies will be carried out on the relationship between APOE and the different results of Covid. “We have taken the first step,” she says. “But to be clinically useful, these results will need to be evaluated in prospective human trials that assess individuals based on their APOE genotypes and take into account the availability of vaccination, something that was not available early in the pandemic and would improve.” the results of Covid in all APOE genotypes.”